ABSTRACT The goal of this work is to apply novel, noninvasive magnetic resonance imaging (MRI) methods for visualizing lymphatic circulation dysfunction to test fundamental hypotheses about lymphedema risk factors and therapies. Breast cancer treatment-related lymphedema (BCRL) arises secondary to surgical axillary lymph node (LN) dissection and irritation, and is a chronic and lifelong condition affecting a high 21.4% of patients receiving common breast cancer therapies. Reducing condition onset and improving management represent major unmet clinical needs for these 50,000 - 80,000 new patients per year, and emerging efforts focus on improving quality of life through more informed LN dissection and biopsy decisions, optimizing post-surgical complex decongestive therapy (CDT), and exploring novel pharmacological and surgical procedures. However, fundamental gaps in our knowledge persist regarding optimized implementation of these therapies and details of the physiological changes they elicit. The major underlying limitation is that there is a shortage of imaging methods available that can be used to evaluate lymphatic function directly, and there is currently no consensus regarding effective outcome measures for therapeutic efficacy evaluation. Rather, LN removal is frequently based on sentinel LN biopsy and additional subjectivity of the surgeon. Therapy evaluation is frequently based on coarse measurements such as changes in limb volume or patient-reported symptoms, which provide little information on underlying mechanistic changes that could be used to further refine these therapies. As part of our ongoing INFORM clinical trial of BCRL progression and therapy, we have demonstrated potential for new, noninvasive MRI approaches to identify BCRL risk in sub-clinical disease stages, as well as to visualize internal changes in lymphatic functioning as a result of emerging therapies. Here, we propose to extend these studies to improve abilities for BCRL theranostics. (Aim 1) Prevention. We will apply new anatomical and functional LN imaging approaches to identify LN profiles specific to biopsy-confirmed metastatic LNs; findings could be used to better inform LN dissection and reduce the incidence of benign LN removal. (Aim 2) Progression. We will improve our understanding of BCRL risk progression by testing the hypothesis that superficial tissue profiles and subcutaneous adipose accumulation are more prevalent in patients experiencing BCRL progression, and thereby could be used to triage patients for aggressive therapies prior to overt symptoms and irreversible damage. (Aim 3) Therapy. We will perform a repeated-measures cross-over trial to test the hypothesis that mobilization of protein enriched hardened tissue using graded negative pressure therapy in conjunction CDT is superior to standard CDT alone. The overall goal is to develop objective markers of lymphatic dysfunction that can be used in emerging therapeutic trials of cancer and BCRL therapies to reduce both the incidence and severity of symptoms associated with this prevalent and chronic condition.